PHAGOCYTIC LINING CELLS DETERMINE LOCAL EXPRESSION OF INFLAMMATION INTYPE-II COLLAGEN-INDUCED ARTHRITIS

Objective. To investigate the in vivo role of phagocytic synovial lini ng cells in the local expression of inflammation in type II collagen-i nduced arthritis (CIA) in DBA/1J mice. Methods. On various days before arthritis induction (day 7, 5, or 2), phagocytic lining cells were se lectively depleted from the synovial layer by injecting multilamellar liposomes containing clodronate (dichloromethylene diphosphonate) dire ctly into the knee joints. As controls, either PBS or PBS-laden liposo mes were injected. CIA was induced by immunizing mice with heterologou s bovine type II collagen in Freund's complete adjuvant. Arthritis ons et was synchronized by a single intraperitoneal injection of lipopolys accharide; arthritis was evaluated in hematoxylin and eosin-stained kn ee joint sections. Chemotactic activity in synovial washout samples wa s detected in a Transwell chemotactic assay. Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) protein levels were measured i n NOB-1 and L929 bioassays, respectively. IL-1 messenger RNA (mRNA) in synovial specimens was measured by reverse transcriptase-polymerase c hain reaction. IL-1 was also detected immunohistologically in knee joi nt sections. Results. In clodronate-laden liposome-treated, lining-dep leted knee joints, there was significantly decreased inflammation comp ared with controls. Cell influx into the synovium was markedly decreas ed. Expression of IL-1 mRNA in the synovium was significantly reduced. IL-1 was detected only in some cells in the deeper synovial layer, in contrast to controls, in which large numbers of cells in the deeper s ynovial layer were stained. In synovial washouts from lining-depleted knee joints, biologically active IL-1 levels were reduced by 40% at 6 hours after arthritis induction. Most strikingly, chemotactic activity was highly decreased in these synovial washout samples. When IL-1 or TNF alpha was injected into the knee joints of immunized mice in which arthritis was not yet expressed, arthritis was not induced in the lin ing-depleted joints, whereas marked cell influx was found in control j oints. Conclusion. Our data indicate that phagocytic lining cells play a crucial role in the local expression of inflammation in systemicall y induced CIA. Phagocytic lining cells probably form an important sour ce of chemotactic factors which are set free upon activation by IL-1 o r TNF alpha.